Regulation of expression of the DNA repair gene-O6-methylguanine-DNA methyltransferase via protein kinase C-mediated signaling

Istvan Boldogh, Chilakamarti V. Ramana, Zhenping Chen, Tapan Biswas, Tapas K. Hazra, Sabine Grösch, Thomas Grombacher, Sankar Mitra, Bernd Kaina

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82 Scopus citations

Abstract

O6-akylguanine is the major mutagenic and cytotoxic DNA lesion induced by alkylating agents, including 2-chloroethyl-N-nitrosaurea-based antitumor drugs. This lesion is repaired by O6-methylguanine-DNA methyltransferase (MGMT), the expression of which is highly variable in both normal tissues and in tumor cells. The promoter of the human MGMT gene was found to contain two putative activator protein (AP)-1 sites. Here, we show that the level of MGMT mRNA in HeLa S3 cells was increased 3-5-fold by phorbol-12-myristate-13- acetate (TPA) and 1,2-diacyl-sn-glycerol (DAG), which are activators of protein kinase C(PKC), as well as by okaidic acid, an inhibitor of protein phosphatases. The PKC inhibitor 1-(5-isoquinoline sulfonyl)-2- methylpiperazine-HCl eliminated MGMT activation by TPA and DAG but not by OA. Prior down-regulation of PKC abolished subsequent effects of TPA or DAG. The results indicate AP-1 to be involved in regulation of MGMT expression. This hypothesis was supported by showing AP-1 binding to two target sequences of the MGMT promoter and transactivation of the MGMT promoter upon cotransfection with c-fos and c-jun in F9 cells. That TPA-mediated induction of MGMT caused increased cellular resistance to 2-chloroethyl-N-nitrosaurea suggest a therapeutic significance for PKC-mediated MGMT modulation.

Original languageEnglish (US)
Pages (from-to)3950-3956
Number of pages7
JournalCancer Research
Volume58
Issue number17
StatePublished - Sep 1 1998

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Boldogh, I., Ramana, C. V., Chen, Z., Biswas, T., Hazra, T. K., Grösch, S., Grombacher, T., Mitra, S., & Kaina, B. (1998). Regulation of expression of the DNA repair gene-O6-methylguanine-DNA methyltransferase via protein kinase C-mediated signaling. Cancer Research, 58(17), 3950-3956.